Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• chirality of the Michael acceptors can be attributed to one of two factors: 1) use of a chiral auxiliary attached to the nitrogen or 2) existing stereochemistry of the acceptor. In this section, we will briefly discuss the use of both types of chiral Michael acceptors in DCA of α,β-unsaturated amides and

• lactams. 1.1 DCA using chiral auxiliaries Chiral auxiliaries have been useful tools to induce stereoselectivity in C–C bond forming reactions [5][32][33][34]. Ideally, these compounds are stable, easily attached, removed and recoverable. One of the first examples of a DCA reaction using a chiral auxiliary

• was done by Mukaiyama and Iwasawa in 1981 [28]. DCA reactions were performed on a series of α,β-unsaturated amides, which employed L-ephedrine as a chiral auxiliary (Scheme 2). Mechanistically, it was supposed that the Grignard reagent formed an internal chelate between the nitrogen and the oxygen on

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• stainless steel cathode were utilised in a flow cell set-up [35]. An important example of the scope and synthetic potential of the silyl electroauxiliary approach was reported by Yoshida (Scheme 5) in combination with a chiral auxiliary a highly diastereoselective cationic carbohydroxylation occurred [18

• –silicon bond (when an electroauxiliary is present) or direct carbon–hydrogen bond fission to afford the α-methoxylated product (Scheme 10) [67][68]. The direct anodic oxidation reaction to afford the N-acyliminium ion can be intercepted with a carbon nucleophile enantioselectively when a chiral auxiliary

• were intercepted with cyanide [71]. The enantioselectivity induced in this step was as a result of using a chiral auxiliary, 8-phenylmenthyl attached to the carbamate (Scheme 19). Other natural product syntheses have used the anodic oxidation approach, often as the first step in a synthesis campaign to

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

• Paweł Borowiecki,
• Daniel Paprocki and
• Maciej Dranka

Beilstein J. Org. Chem. 2014, 10, 3038–3055, doi:10.3762/bjoc.10.322

• substituents with a minimum of experimental work being invested as long as reliable CDA is employed. In all of our previous studies α-methoxy-α-phenylacetic acid (O-methylmandelic acid, MPA) used in both enantiomeric forms turned out to be an excellent chiral auxiliary reagent for this type of derivatized

• phenyl ring of the chiral auxiliary regent MPA), showed appropriate strength (intensity) giving rise to perceptible shifts in the 1H NMR signals of the L1/L2 groups located close to the chiral carbon in each of the investigated derivatives 11 and 12. (iii) The 1H NMR signals of the chiral MPA shift

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• corresponding (2S,1'S,2'R)- [see Scheme 3, derived from (S)-10] and (2R,1'S,2'R)-3-(2'-fluoromethylcyclopropyl)alanines [derived from (R)-10] in good to excellent yields. The chiral auxiliary was recovered as the hydrochloride of 2-[(N-benzylprolyl)amino]benzophenone (~95%). (R)-allo-Threonine (4) is

• with alkyl halides virtually yield single stereoisomers, in which the configuration of the newly formed stereogenic center at C-2 of the amino acid moiety is the same as that in the proline moiety of the chiral auxiliary in the starting material. In reactions of the enolate of this chiral glycine

• . Bearing in mind that the starting materials are inexpensive and the chiral auxiliary is reusable (≥95% recovery), this protocol represents one of the best routes to the rather expensive (R)-allo-threonine (4). It is also possible to obtain (R)-allo-threonine starting from (R)-10 and acetaldehyde under

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• the natural product. Contrasting Meyers’ approach, which employed a chiral auxiliary as part of 39, we thought a catalytic enantioselective alkylation strategy would be ideal for a formal total synthesis of natural (−)-aspidospermine (36) via the antipode of 38. The formal synthesis began with 1,3

• using a chiral auxiliary strategy. We envisioned that chiral lactam 60 could again be readily accessed by our palladium-catalyzed enantioselective alkylation chemistry. The formal synthesis of (−)-vincadifformine commenced with ruthenium-catalyzed isomerization of the terminal olefin moiety in

• . Additionally, a rapid approach to a compound in Meyers’ formal synthesis of (+)-aspidospermine (36) granted access to the natural product without the use of a chiral auxiliary. Finally, we have demonstrated the application of lactam alkylation products in the catalytic asymmetric syntheses of (+)-rhazinilam

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• bearing the chiral auxiliary can be cleaved by ozonolysis to the corresponding aldehydes 36 and the latter reduced to alcohols 37, respectively, as shown in Scheme 4. Many highly functionalized, vicinally substituted compounds could be prepared by this method in good to excellent enantiopurity [37][38][39

• butenolide 83 in hand the stage was set for one of the key steps of the synthesis. Addition of the anion of phosphonamide 28c to 83 proceeded with a high level of facial and cis/trans-selectivity to afford adduct 88 as a single diastereomer with the correct stereochemistry. Removal of the chiral auxiliary by

• chiral auxiliary and oxidized to diacid 99. Converison into its potassium salt yielded squalene synthase inhibitor (S)-19. In a similar sequence, the minor diastereomer from the sulfuration, 1-epi 98, was converted into the opposite enantiomer (R)-19 (Scheme 12A). Reversing the steps for the introduction

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• asymmetric Strecker reaction, in which an (S)-α-phenylethylamine was employed as the chiral auxiliary [4]. In this reaction, he obtained a chiral alanine with 95% optically activity; see Scheme 2. In 1996, Lipton et al. succeeded in a series of asymmetric Strecker reactions by employing a chiral catalyst, a

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• (S)-4 to obtain 5, was achieved by treatment with N-methylpyrrolidine. An alternative method is based on ephedrine as a chiral auxiliary and was developed by Genêt and Jugé [36][37]. The key synthetic intermediates in this approach are 1,3,2-oxazaphospholidine boranes 7. These compounds are the

• for the synthesis of P-stereogenic phosphines by adding a catalytic amount of a chiral auxiliary. The enantioenriched phosphine 108 was obtained through coupling of racemic bulky secondary phosphine 107 with PhI in the presence of the base NaOSiMe3 and the Pd-catalyst (Scheme 30) [201]. In the

Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines

• Jian-bo Xie,
• Jian Luo,
• Timothy R. Winn,
• David B. Cordes and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 746–751, doi:10.3762/bjoc.10.69

• the treatment of multiple myeloma and mantle cell lymphoma [21]. This product is usually synthesized in three representative processes: (1) to use (1S,2S,3R,5S)-(+)-2,3-pinanediol as the chiral auxiliary for the addition reaction followed by chlorination and amination [14][15]; (2) to perform copper

Synthesis of chiral N-phosphinyl α-imino esters and their application in asymmetric synthesis of α-amino esters by reduction

• Yiwen Xiong,
• Haibo Mei,
• Lingmin Wu,
• Jianlin Han,
• Yi Pan and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 653–659, doi:10.3762/bjoc.10.57

• protected α-amino ester 4. Typical sulfinyl (a), phosphonyl aldimines (b) and phosphinyl imino esters (c). Synthesis of α-imino ester by rearrangement. Cleavage of the chiral auxiliary. Optimization of the synthesis of α-imino ester 3a by the condensation method.a Synthesis of N-phosphinyl-protected α-imino

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• , thioacetic acid and 4-methoxy-phenylethylamine (also as chiral auxiliary) provided the corresponding Ugi product 138 in 60% yield (dr 1:1). Chiral separation and deprotection in TFA resulted in compound 139 in 70% yield, after which saponification followed by an amide coupling with tryptamine and CDI

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• , as a chiral auxiliary it promotes the cycloaddition governing the stereochemistry of the process. The chiral auxiliary can be removed at the end of the reaction. Another interesting peculiarity concerns the exceptionally mild reaction conditions preventing unwanted aldehyde/enol or imine/enamine

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen

• Hiroki Moriwaki,
• Daniel Resch,
• Hengguang Li,
• Iwao Ojima,
• Ryosuke Takeda,
• José Luis Aceña and
• Vadim A. Soloshonok

Beilstein J. Org. Chem. 2014, 10, 442–448, doi:10.3762/bjoc.10.41

• novel and advanced structural type of Ni(II) complexes using an inexpensive and nonracemizable chiral auxiliary. As the first step in this direction, here we describe the preparation of Ni(II) complexes of glycine Schiff base with α-phenylethylamine-derived ligands. One unusual feature of these new

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• by using a chiral auxiliary (>95% de in the case of an L-proline-derived diene). Diversification on the different units, diene, dienophile and aldehyde, has been described. Concerning the maleimide material, substituent R3 did not exert any significant effect on the process. Other dienophiles have

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• [115][116], bearing a chiral auxiliary [117]. The intermediate cis-divinylcyclopropane 129 rearranged to the corresponding bridged cycloheptadiene 130 in a DVCPR. The chiral auxiliary was removed in the following using methanolysis conditions, followed by reduction of the more electron rich double bond

• towards the total synthesis of salvileucalin B (292, see Scheme 35) isolated from the plant Salvia leucantha [213]. Starting from enantiopure trialkyne 282, desilylation was affected using TBAF, followed by ruthenium-catalyzed cycloisomerization [214] and cleavage of the chiral auxiliary to obtain

Plakilactones G and H from a marine sponge. Stereochemical determination of highly flexible systems by quantitative NMR-derived interproton distances combined with quantum mechanical calculations of ¹³C chemical shifts

• Simone Di Micco,
• Angela Zampella,
• Maria Valeria D’Auria,
• Carmen Festa,
• Simona De Marino,
• Raffaele Riccio,
• Craig P. Butts and
• Giuseppe Bifulco

Beilstein J. Org. Chem. 2013, 9, 2940–2949, doi:10.3762/bjoc.9.331

• the cis-isomer allowing us to suggest a 7,8-erythro relative stereochemistry. The application of the double derivatization method with a chiral auxiliary reagent developed by Riguera [30] allows for the confirmation of the relative configuration at C-7 and C-8 and the assignment of the absolute

• the double derivatization method with a chiral auxiliary reagent and the results were fully in agreement with the relative configuration of the epoxide moiety on the plakilactone H side chain. Subsequently, the absolute configuration at C-4 and C-6 was obtained through QM calculations of 13C chemical

Stereodivergent synthesis of jaspine B and its isomers using a carbohydrate-derived alkoxyallene as C₃-building block

• Volker M. Schmiedel,
• Stefano Stefani and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2013, 9, 2564–2569, doi:10.3762/bjoc.9.291

• jaspine B (1) as an attractive target [29][30][31][32][33]. Our approach to 1 is based on the addition of a lithiated alkoxyallene with a chiral auxiliary to pentadecanal as electrophile. This step will generate the first stereogenic center and install the C14-alkyl chain at the later C-2 position of the

Non-cross-linked polystyrene-supported 2-imidazolidinone chiral auxiliary: synthesis and application in asymmetric alkylation reactions

• Quynh Pham Bao Nguyen and
• Taek Hyeon Kim

Beilstein J. Org. Chem. 2013, 9, 2113–2119, doi:10.3762/bjoc.9.248

• -imidazolidinone chiral auxiliaries were successfully investigated with excellent diastereocontrol (>99% de). The recovery and the recycling of this soluble polymer-supported chiral auxiliary were achieved in order to produce highly optical pure carboxylic acids. Keywords: asymmetric alkylation; chiral

• for asymmetric synthesis, into the solid support [18][19]. As a part of our ongoing research, we herein report a novel NCPS-supported 2-imidazolidinone chiral auxiliary that exhibited excellent diastereocontrol. Its recycling and reuse for the synthesis of several chiral carboxylic acids are addressed

• . Results and Discussion First, the 2-imidazolidinone chiral auxiliary 1 was prepared in the solution phase from the commercially available O-benzyl-L-tyrosine in four steps, as previously reported [18]. For the synthesis of our envisioned homogeneous polymer, we began to directly co-polymerize a pair of

An investigation of the observed, but counter-intuitive, stereoselectivity noted during chiral amine synthesis via N-chiral-ketimines

• Thomas C. Nugent,
• Richard Vaughan Williams,
• Andrei Dragan,
• Alejandro Alvarado Méndez and
• Andrei V. Iosub

Beilstein J. Org. Chem. 2013, 9, 2103–2112, doi:10.3762/bjoc.9.247

• unequivocally supported this conclusion. The present study co-examines an alternative hypothesis, namely that some classes of cis-imines may hold conformations that erode the inherent facial bias of the chiral auxiliary, providing more of the trans-imine reduction product than would otherwise be expected. The

A practical synthesis of long-chain iso-fatty acids (iso-C₁₂–C₁₉) and related natural products

• Mark B. Richardson and
• Spencer J. Williams

Beilstein J. Org. Chem. 2013, 9, 1807–1812, doi:10.3762/bjoc.9.210

• a single diastereoisomer (as determined by 1H NMR) in 80% yield. Cleavage of the chiral auxiliary using LiOH/H2O2 (which occurs without racemization at the α-position) [64] afforded (S)-2,15-dimethylpalmitic acid (30) in 98% yield. 2-Hydroxy-15-methylpalmitic acid has been identified from a range of

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• functionalized ketone by oxy-Michael addition. Synthesis of ketone 57 using thiazolidinethione chiral auxiliary. Synthesis of β-ketoester 61. Decarboxylation of 61 under Krapcho conditions. Improved synthesis of 63 and attempted iodocyclization. Synthesis of cyanohydrin acetonide and attempted alkylation with

• the known allylic alcohol [58]. To synthesize ketone 57, we opted to utilize an asymmetric aldol reaction to set the stereochemistry of the β-hydroxy group. Since the report of Evans’s diastereoselective asymmetric aldol reaction using the boron enolates of N-acyloxazolidinones [59], numerous chiral

• -auxiliary-based methods have been developed for the synthesis of syn- or anti-propionate aldol units. However, many of these auxiliaries, including the Evans oxazolidinones, fail to give high stereoselectivities when employed in acetate aldol reactions [60]. Of the methods available, we selected Sammakia’s

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

• Tomoko Yajima,
• Eriko Yoshida and
• Masako Hamano

Beilstein J. Org. Chem. 2013, 9, 1432–1436, doi:10.3762/bjoc.9.161

• as a single diastereomer [11][12] (Scheme 2). Hydrolysis with CF3CO2H and converting the hydroxy group to the chloride yielded the corresponding lactam 9 [13]. The chiral auxiliary was removed by DBU-assisted elimination to the enamine and subsequent hydrolysis [14]. Introducing the pivaloyl group

Exploration of an epoxidation–ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

• Brad M. Loertscher,
• Yu Zhang and
• Steven L. Castle

Beilstein J. Org. Chem. 2013, 9, 1179–1184, doi:10.3762/bjoc.9.132

• stereocenter of 13 was assigned based on the established stereochemical course of the Myers alkylation [23]. Finally, reductive removal of the chiral auxiliary with lithium amidotrihydroborate [26] produced alcohol 14, and benzylation yielded triether 15. Asymmetric epoxidation of alkene 15 was somewhat

• , we installed a TIPS group on alcohol 11 (Scheme 5). Gratifyingly, TIPS-protected amide 20 was alkylated by 8 in the same yield as TBDPS-protected amide 12. Reductive removal of the chiral auxiliary furnished alcohol 22 in 91% yield. Fortunately, naphthylmethylation of 22 was achieved without

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

• Julien Lefranc,
• Alberto Minassi and
• Jonathan Clayden

Beilstein J. Org. Chem. 2013, 9, 628–632, doi:10.3762/bjoc.9.70

• undergo enantioselective carbolithiation in the presence of (−)-sparteine or a (+)-sparteine surrogate [4], but enantioselective carbolithiation of carbamate 9 in the presence of (−)-sparteine led to product with only 60:40 er. The use of a chiral auxiliary in the form of a (−)-menthylcarbamate (11) also

Regio- and stereoselective carbometallation reactions of N-alkynylamides and sulfonamides

• Yury Minko,
• Morgane Pasco,
• Helena Chechik and
• Ilan Marek

Beilstein J. Org. Chem. 2013, 9, 526–532, doi:10.3762/bjoc.9.57

• carbocupration reaction is again at the center of interest but this time for the regioselective addition of organocopper derivatives to various ynamide species. Particularly interesting is the carbocupration of N-alkynyl carbamates 7, bearing Evans’s oxazolidinone chiral auxiliary, which leads to the formation